dbSNP rs104893941: SQSTM1:p.Pro392Leu (chr5-179836445-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS3PM1PP5BP4

The NM_003900.5(SQSTM1):c.1175C>T(p.Pro392Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,614,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000456921: Functional studies demonstrated that the p.Pro392Leu variant disrupted protein interaction and reduced binding affinity for ubiquitin (Cavey et al. 2005" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P392P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:4

Conservation

PhyloP100: 7.87

Publications

158 publications found

Variant links:

Genes affected

SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

SQSTM1 links:

MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]

MRNIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000456921: Functional studies demonstrated that the p.Pro392Leu variant disrupted protein interaction and reduced binding affinity for ubiquitin (Cavey et al. 2005; Rea et al. 2006; Chamoux et al. 2009; Kurihara et al. 2011; Sundaram et al. 2011).; SCV001550746: Other in vitro functional expression studies in E. coli showed the p.P392L mutation caused loss of monoubiquitin binding and impaired K48-linked polyubiquitin binding (Cavey_2005_PMID:15765181).; SCV000245666: "In vi tro and in vivo functional studies support an impact on protein function (Layfield 2004, Hiruma 2008, Chamoux 2009, Kurihara 2011; Daroszewska 2018)"; SCV000774416: Experimental studies have shown that this missense change affects SQSTM1 function (PMID: 15765181, 16813535, 19589897, 21195346, 21878516).; SCV005900376: Knock-in mouse models assessing the murine equivalent of the variant suggests it increases osteoclastogenesis but does not induce PDB alone (PMID: 18765443, 21195346, 21515589).

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_003900.5

PP5

Variant 5-179836445-C-T is Pathogenic according to our data. Variant chr5-179836445-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8108.

BP4

Computational evidence support a benign effect (MetaRNN=0.09615874). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SQSTM1	NM_003900.5	MANE Select	c.1175C>T	p.Pro392Leu	missense	Exon 8 of 8	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2		c.923C>T	p.Pro308Leu	missense	Exon 9 of 9	NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2		c.923C>T	p.Pro308Leu	missense	Exon 9 of 9	NP_001135771.1	Q13501-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.1175C>T	p.Pro392Leu	missense	Exon 8 of 8	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5	TSL:1	c.923C>T	p.Pro308Leu	missense	Exon 7 of 7	ENSP00000353944.5	Q13501-2
MRNIP	ENST00000522663.5	TSL:1	n.*1245G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000429835.1	F6UWW1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00531

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000980

AC:

246

AN:

251018

AF XY:

0.000987

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00143

AC:

2091

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1013

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00170

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000336

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00168

AC:

1865

AN:

1112012

Other (OTH)

AF:

0.00156

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

135

270

406

541

676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152272

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41554

American (AMR)

AF:

0.00530

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00162

AC:

110

AN:

68022

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00196

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.000889

AC:

108

EpiCase

AF:

0.00158

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (3)

Paget disease of bone 3 (3)

Amyotrophic lateral sclerosis (1)

Bone Paget disease (1)

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (1)

Paget disease of bone 3;C4225326:Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (1)

Spastic paraplegia-Paget disease of bone syndrome (1)

SQSTM1-related multisystem proteinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.096

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.7

PhyloP100

7.9

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0020

Sift4G

Benign

0.070

Polyphen

0.99

Vest4

0.92

MVP

0.99

MPC

0.59

ClinPred

0.13

GERP RS

4.8

Varity_R

0.72

gMVP

0.51

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over